PROJECT SUMMARY/ABSTRACT Asthma symptom control is suboptimal in the majority of children in the United States, despite widespread availability of asthma controller medications and standardized treatment guidelines. While deaths from asthma have declined, more than 50% of children with asthma experience an exacerbation each year and the public health burden is substantial. While the factors associated with asthma symptom control are complex, it is also recognized that children with exacerbation-prone asthma are a heterogeneous group, with differing symptom profiles that may contribute to differing clinical outcomes. However, existing research on asthma symptoms in this age group is quite limited and has focused primarily on respiratory symptoms in isolation, ignoring other physical symptoms and symptoms of mental and social health that are important to overall functional status and quality of life. To date, there has been no attempt to comprehensively identify and phenotype symptom clusters (defined as two or more concurrent symptoms independent of other clusters) in children with exacerbation-prone asthma. Given this major shortcoming, this 48-week cohort study (N=173) will test the overarching hypothesis that symptom clusters and their associated inflammatory and metabolic pathways predict corticosteroid treatment responsiveness (primary objective outcome) and quality of life (patient-reported secondary outcome) in children 8-17 years with exacerbation-prone asthma. Specific aims are to: 1) identify and phenotype symptom clusters and assess their temporal trajectories, 2) determine associations between symptom clusters and clinical outcomes, and 3) identify inflammatory and metabolic pathways underlying symptom clusters in children with exacerbation-prone asthma. We anticipate that a cluster of children with the poorest physical, mental and social health symptoms will emerge; we further anticipate that the symptom presentations in this cluster of children will be stable over time and will result in the poorest corticosteroid treatment responsiveness, the poorest quality of life, and the greatest magnitude of inflammation. This project involves a multidisciplinary team with a history of collaboration and is aligned with the NINR Strategic Plan to “Advance Symptom Science Research” in chronic conditions through biobehavioral research. Expected deliverables from this project include: 1) refined knowledge regarding the identification and clinical utility of symptom clusters in children with exacerbation-prone asthma, and 2) identification of mechanisms underlying symptom clusters that can be targeted in future interventional studies. Because children with exacerbation- prone asthma rarely report a single symptom, these discoveries have the potential to significantly advance individualized treatment and improve clinical outcomes, ultimately reducing the high morbidity and improving quality of life in affected children.